From the Duke Clinical Research Institute, Duke University, Durham, NC (Dr Jollis); Medical Review of North Carolina Inc, Cary (Drs Simpson and Chowdhury); Division of Cardiology (Drs Simpson, Cascio, and Smith) and Department of Epidemiology (Dr Massing), University of North Carolina, Chapel Hill; and the Department of Medicine, Wake Forest University School of Medicine, Winston-Salem, NC (Dr Crouse).

ResultsCalcium channel blockers were widely prescribed at hospital discharge to elderly patients with myocardial infarction between 1994 and 1995 (n = 51,921), the most commonly prescribed being diltiazem (n = 21,175), nifedipine (n = 12,670), amlodipine (n = 11,683), and verapamil (n = 3639). After adjusting for illness severity and concomitant medication use, patients who were prescribed calcium channel blockers at hospital discharge did not have increased risk for 30-day or 1-year mortality, with the exception of the few (n = 116) treated with bepridil. Bepridil differs from other calcium channel blockers because of its tendency to prolong repolarization, and its association with proarrhythmic effects in elderly patients.

ConclusionWe did not identify a mortality risk in a large consecutive sample of elderly patients with myocardial infarction, which supports the need for additional prospective trials examining calcium channel blocker therapy for ischemic heart disease.

Figures in this Article

CALCIUM CHANNEL blockers represent a potentially useful therapy for elderly patients with coronary artery disease, given their ability to relieve angina, lower blood pressure, and slow conduction of atrial fibrillation. However, growing evidence has cast doubt on their safety. In post hoc analyses, the Multicenter Diltiazem Postinfarction Trial (MDPIT)1 found higher rates of nonfatal reinfarction or cardiac death associated with diltiazem treatment in patients with myocardial infarction (MI) and pulmonary congestion or reduced ejection fraction. More recently, a meta-analysis2 of nifedipine therapy after acute MI identified higher mortality associated with nifedipine therapy on a dose-response basis. These findings have led to much uncertainty regarding calcium channel blocker therapy, and further studies involving large numbers of patients are needed to examine the safety of their use. Given current apprehension among clinicians regarding calcium channel blocker therapy, such studies are unlikely to be performed, particularly involving formulations for which patents have expired. Decisions regarding the use of calcium channel blockers in the elderly are even more difficult, given the relatively few elderly patients enrolled in previous trials. In 1995, calcium channel blockers—including nifedipine, diltiazem, and verapamil—were widely used among Medicare patients. We examined the relationship between calcium channel blocker use after acute MI and survival for 141,041 elderly patients, as part of the Health Care Financing Administration's Cooperative Cardiovascular Project (CCP). The propensity model included all variables in the mortality model, plus revascularization procedures after admission (bypass surgery and angioplasty) and hospital discharge medications (aspirin, β-adrenergic blocking agents, and angiotensin-converting enzyme inhibitors).

PATIENTS AND METHODS

PATIENT POPULATION

The CCP abstracted hospital charts of Medicare patients with a principal diagnosis of acute MI (International Classification of Diseases codes 410.x0 and 410.x1) consecutively discharged from the hospital during 8-month periods between 1994 and 1995, in 46 states.3- 5 Information collected for each Medicare patient included patient identifiers, hospitalization dates, demographics, chest pain history, physical examination findings, medications used, presence or absence of contraindications to therapy, electrocardiograms, cardiac enzyme levels, treatment, complications, and survival status. Accuracy of hospital chart abstraction was evaluated on a monthly basis by masked reabstraction, with agreement rates by data element in the 85% to 95% range. Calcium channel blockers were identified at 2 points in the CCP chart abstraction, according to discharge medications entered by free text and by a specific variable for "calcium channel blocker at discharge." These 2 variables agreed for 51,843 of 51,921 patients we identified as being treated with calcium channel blockers, and for 89,099 of 89,120 patients not being treated. All patients older than 65 years who were discharged from the hospital alive were included in the present study. Dates of death were obtained from the Medicare Enrollment Database and the Social Security Administration's Master Beneficiary Record File.

DATA ANALYSIS

The primary analysis of the present study compared the mortality of patients who were prescribed calcium channel blockers at hospital discharge after acute MI with that of patients discharged but not taking these drugs. Calcium channel blockers were classified as nifedipine, amlodipine, other dihydropteridines, diltiazem, verapamil, and bepridil hydrochloride. Baseline characteristics and outcomes were compared between treatment categories using χ2 tests for categorical variables and analysis of variance for continuous variables.

Thirty-day and 1-year mortality after hospital discharge were examined in logistic regression models after adjusting for illness severity, medications taken, and propensity for treatment with calcium channel blockers (propensity score). Logistic model variables were selected on the basis of their association with mortality according to previous work, strength of association, and clinical intuition (Table 1 and Table 2). Specific model components included age, sex, race, descriptors of MI and coronary disease severity, comorbid illnesses, mobility at discharge, discharge destination, and propensity score. Propensity score was derived according to the methods of Rubin6 using an additional logistic model to examine characteristics associated with being discharged while taking a calcium channel blocker.7 Component variables for the propensity model were selected in a similar manner as those for the mortality models, using association with calcium channel blocker therapy as the gauge of importance (Table 3).

RESULTS

PATIENT CHARACTERISTICS

A total of 141,041 patients with acute MI who survived to hospital discharge were included in this study (Table 4 and Table 5). Of these patients, 51,921 were prescribed calcium channel blockers at hospital discharge, the most commonly diltiazem (21,175 patients), nifedipine (12,670 patients), amlodipine (11,683 patients), and verapamil (3639 patients). Compared with patients who were not prescribed calcium channel blockers at hospital discharge, these patients were similar in age; more likely to have had a non–Q wave MI, hypertension, and previous coronary disease; and less likely to have a low, left ventricular ejection fraction or to have developed shock or congestive heart failure during hospitalization. Patients treated with calcium channel blockers were also less likely to be prescribed β-adrenergic blocking agents or angiotensin-converting enzyme inhibitors at hospital discharge, or to have undergone bypass surgery.

Among patients who were prescribed calcium channel blockers at hospital discharge, those treated with amlodipine were most likely to have rales, congestive heart failure, or a low ejection fraction, whereas those treated with diltiazem were least likely to have these conditions. Patients prescribed nifedipine at hospital discharge were most likely to have hypertension and to be prescribed β-adrenergic blocking agents. According to the propensity model, blood pressure, left ventricular ejection fraction greater than 40%, and non–Q wave MI had the strongest associations with calcium channel blocker treatment at hospital discharge (Table 3).

MORTALITY

Crude 30-day and 1-year mortality rates were lower for patients who were prescribed calcium channel blockers at hospital discharge compared with those discharged but not taking such drugs (Table 5). The lowest unadjusted 30-day and 1-year mortality rates were seen in nifedipine- and diltiazem-treated patients. By 1 year, 61 (52.6%) of 116 patients discharged while taking bepridil had died compared with 29,361 of 141,041 (a 20.8% mortality rate) for the entire cohort.

After adjusting for illness severity, medications used, and treatment propensity, the likelihood of death at 30 days or 1 year for patients who were prescribed calcium channel blockers at hospital discharge was similar to that for those not treated (Figure 1 and Figure 2). Stratifying the adjusted analyses according to the most commonly prescribed calcium channel blockers (diltiazem, nifedipine, amlodipine, and verapamil), all 95% confidence intervals overlapped 1, consistent with no statistically significant differences in mortality. However, trends for mortality for amlodipine-treated patients were somewhat higher at 30 days and, for verapamil-treated patients, were somewhat lower at 1 year.

Place holder to copy figure label and caption

Figure 1.

Relative likelihood of 30-day mortality for patients who were prescribed calcium channel blockers at hospital discharge vs those not prescribed.

Bepridil therapy represented an exception to the lack of association between calcium channel blocker therapy and mortality. Mortality for 116 patients who were prescribed bepridil at hospital discharge was substantially higher than for 116 control patients matched for age and illness severity (30-day mortality, 13.8% vs 4.3%; P<.01, and 1-year mortality, 52.6% vs 27.6%; P<.001).

COMMENT

Calcium channel blockers were widely prescribed at hospital discharge to elderly patients with MI between 1994 and 1995. With the exception of the few patients treated with bepridil, this treatment was not associated with increased mortality. After adjusting for illness severity and concomitant medication use, the one third of patients with MI who were prescribed calcium channel blockers at hospital discharge had similar 1-year mortality rates as those discharged but not taking these drugs. This failure to identify a mortality risk in a large, consecutive sample of elderly patients with MI suggests that calcium channel blockers—particularly diltiazem, nifedipine, amlodipine, and verapamil—can be used to treat angina, hypertension, and atrial fibrillation in elderly patients with MI without adversely affecting their 1-year mortality. The negative findings further support the need for additional prospective trials examining calcium channel blocker therapy in ischemic heart disease.

POTENTIAL EXPLANATIONS FOR FINDINGS

There are several potential explanations for why we did not identify a mortality risk with calcium channel blocker therapy. The first explanation may be that, despite concerning findings in some previous studies, calcium channel blocker therapy does not increase mortality after MI. Primary analyses of 2 randomized controlled trials, the MDPIT1 and the Danish Verapamil Infarction Trial,8 did not identify excess mortality associated with long-term diltiazem or verapamil therapy, respectively. Meta-analyses by Held et al9 and Pepine et al10 and a cohort study by Braun et al11 also did not detect a mortality association for calcium channel blocker therapy. Our findings might differ from the meta-analysis by Furberg et al2 that found dose-related mortality for short-acting nifedipine because of changes in drug formulation. In 1989, longer-acting nifedipine formulations became available; several investigators12- 15 have since suggested that longer-acting preparations might have sufficiently different pharmacodynamic properties so as to result in lower mortality rates. We had limited information regarding the specific formulation of the nifedipine that our patients took. For 33% of nifedipine-treated patients, long-acting formulations were indicated by text such as "Procardia XL" or "nifedipine GITS," but we cannot determine whether the remaining patients were treated with long-acting formulations—for which documentation was not specific—or short-acting preparations. Based on our data, we can only assert that increased mortality was not seen for patients of whom a substantial portion were discharged while taking long-acting nifedipine formulations.

Our study design might also have impacted our findings. As in all observational cohort studies, it is possible that these findings might have been caused by confounding or insufficient consideration of a factor related to both the selection of calcium channel blockers and mortality. Our approach was designed to limit the possibility of confounding. The CCP identified an extensive amount of pertinent illness severity and medication data, and the similar prevalence of these characteristics compared with other MI cohorts suggests that the measures were reliable.16,17 With the CCP data, we specifically considered factors that led to the selection of calcium channel blockers using the propensity model. After this initial adjustment to compare patients with a similar likelihood of treatment, we used a second regression model to further adjust for factors related to mortality. The ability of our approach to identify mortality risk factors was demonstrated by models that indicated higher mortality for all other factors known to be associated with greater risk.

Because we had a 90% chance of identifying a 1% difference in 1-year mortality at the 95% confidence level, if adequate data were available to balance comparisons, we were unlikely to lack adequate sample size to identify a clinically significant mortality effect for calcium channel blockers. The study lacked information about compliance during the year, and without such information, we cannot be sure that the lack of difference in 1-year mortality was not related to discontinuation of calcium channel blocker therapy in the treated cohort or initiation of such therapy in the untreated cohort.

Our findings might also have been affected by clinicians avoiding calcium channel blocker therapy in patients whom they believed were likely to have adverse outcomes with such therapy. Findings of the MDPIT1 regarding increased mortality with low ejection fraction or pulmonary congestion were published in 1988, 6 years before the start of our study. The propensity models confirmed that patients with pulmonary congestion or congestive heart failure were less likely to be prescribed calcium channel blockers at hospital discharge, suggesting that the MDPIT affected treatment selection. However, there still were many patients with pulmonary congestion or congestive heart failure who were prescribed calcium channel blockers at hospital discharge, making treatment selection an unlikely explanation for the lack of mortality difference.

Our population of elderly patients is a final explanatory factor for our findings. Hypertension and strokes are more common in the elderly.18 In this elderly cohort, calcium channel blocker therapy might have played a greater role in lowering blood pressure and preventing fatal strokes compared with their effect in younger patients typically included in randomized trials (mean age, 58 years; fewer than 15% were >69 years in the MDPIT1). In this scenario, such a benefit might have offset potential deleterious effects of calcium channel blocker therapy observed in younger cohorts, resulting in the absence of a net mortality risk in the elderly.

BEPRIDIL

Although few patients were treated with bepridil, the extraordinarily high 1-year mortality rate associated with this therapy is concerning. Bepridil, like other calcium channel blockers, inhibits voltage-dependent L-type calcium channels, but, unlike other calcium channel blockers, it also has a propensity to inhibit myocardial repolarization and to lengthen the QT interval.19 The drug has also been associated with torsade de pointes, particularly in patients older than 70 years.20 The increased mortality with bepridil therapy in this elderly cohort is consistent with QT prolongation and proarrhythmia. Underlying disease severity may also explain the high mortality observed with bepridil therapy. Patients selected for bepridil therapy were older and more likely to have diabetes, previous MI, and previous congestive heart failure than were all other patients. Although adjustment for differences in patient characteristics did not account for the excess mortality, it is possible that additional factors related to the selection of bepridil therapy and mortality that were not included in our data led to the worse outcome. Given the small number of patients who were prescribed bepridil at hospital discharge, it is also possible that the high mortality rate is a spurious finding. With previous studies identifying an association with torsade de pointes, as well as the extremely high mortality of bepridil-treated patients in our study compared with matched controls, the safety of this drug after MI should be further investigated.

CONCLUSIONS

We examined more than 50,000 elderly patients with MI who were prescribed calcium channel blockers at hospital discharge and found no evidence of increased mortality, except for the few patients treated with bepridil, a drug that is also associated with proarrhythmia. Our findings suggest that calcium channel blockers—particularly diltiazem, nifedipine, amlodipine, and verapamil—can be used to treat angina, hypertension, and atrial fibrillation among elderly patients with MI without adversely affecting mortality. These negative findings also support the need for additional prospective trials examining the efficacy of commonly prescribed calcium channel blockers in ischemic heart disease.

The conclusions and opinions expressed and the methods used herein are those of the authors. They do not necessarily reflect Health Care Financing Administration policy, and the authors assume full responsibility for the accuracy and completeness of the ideas presented. This article is a direct result of the Health Care Quality Improvement Program initiated by the Health Care Financing Administration, which has encouraged identification of quality improvement projects derived from analysis of patterns of care, and therefore required no special funding on the part of this contractor. We welcome ideas and contributions to the corresponding author concerning experiences in engaging with the issues presented.

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